The 3,7-diazabicyclo[3.3.1]nonane scaffold for subtype selective nicotinic acetylcholine receptor ligands. Part 2: Carboxamide derivatives with different spacer motifs

3,7-Diazabicyclo[3.3.1]nonane (bispidine) based nicotinic acetylcholine receptor (nAChR) ligands have been synthesized and evaluated for nAChRs interaction. Diverse spacer motifs were incorporated between the hydrogen bond acceptor (HBA) part and a variety of substituted (hetero)aryl moieties. Bispidine carboxamides bearing spacer motifs often showed high affinity in the low nanomolar range and selectivity for the α4β2¹ nAChR. Compounds 15, 25, and 47 with K_i values of about 1 nM displayed the highest affinities for α4β2¹ nAChR. All evaluated compounds are partial agonists or antagonists at α4β2¹, with reduced or no effects on α3β4¹ with the exception of compound 15 (agonist), and reduced or no effect at α7 and muscle subtypes.     

Novel nicotinic acetylcholine receptor agonists containing carbonyl moiety as a hydrogen bond acceptor

A novel series of α4β2 nAChR agonists lacking common pyridine or its bioisosteric heterocycle have been disclosed. Essential pharmacophoric elements of the series are exocyclic carbonyl moiety as a hydrogen bond acceptor and secondary amino group within diaza- or azabicyclic scaffold. Computer modeling studies suggested that molecular shape of the ligand also contributes to promotion of agonism. Proof of concept for improving working memory performance in a novel object recognition task has been demonstrated on a representative of the series, 3-propionyl-3,7-diazabicyclo[3.3.0]octane (34).